Newton001 Understanding Antimicrobial Resistance Mutations in Tuberculosis: Towards Personalised Treatment to Combat Multi-drug Resistance
Lead Research Organisation:
University of Cambridge
Department Name: Medicine
Abstract
Tuberculosis is recognised as one of Brazil's leading infectious diseases, with over 70,000 cases notified each year. There has been a significant increase in the number of diagnosed Multidrug resistant TB cases, with 10% of those also resistant to the two most important second---line class drugs (XDR-TB). This project aims to build upon existing collaborative programs on understanding effects of mutations, and on combating multidrug resistant and extensively drug resistant (MDR and XDR respectively) tuberculosis (TB). The two nodes, Brazil and UK, have complementary skills that encompass epidemiology, human and pathogen genetics, bioinformatics, structural biology and drug discovery. This multidisciplinary combination will facilitate the development of a novel platform to rapidly identify resistant TB from genomic sequencing. Novel mechanisms of drug resistance in TB will be explored using cutting edge techniques and correlated with clinical outcomes. This will help guide more suitable patient treatment, public health policies and future drug discovery efforts, with potential to bring benefit to individuals and public health in Brazil and UK, providing solutions to a problem that affects a third of the world's population.
Technical Summary
Tuberculosis is recognised as one of Brazil's leading infectious diseases, with over 70,000 cases notified each year. There has been a significant increase in the number of diagnosed MDR-TB cases, with 10% of those also resistant to the two most important second-line class drugs (XDR-TB). In line with WHO Stop TB Strategy, our partnership will focus on emerging sequence-based diagnostics to improve accuracy of individual patient treatment. This project aims to build upon existing collaborative programs on understanding effects of mutations, and on combating multidrug resistant and extensively drug resistant (MDR and XDR respectively) tuberculosis (TB). The two nodes, Brazil and UK, have complementary skills that encompass epidemiology, human and pathogen genetics, bioinformatics, structural biology and drug discovery. This multidisciplinary combination will facilitate the development of a novel platform to rapidly identify resistant TB from genomic sequencing. Novel mechanisms of drug resistance in TB will be explored using cutting edge techniques and correlated with clinical outcomes. This will help guide more suitable patient treatment, public health policies and future drug discovery efforts, with potential to bring benefit to individuals and public health in Brazil and UK, providing solutions to a problem that affects a third of the world's population.
Specific aims:
i)Enhance an existing research partnership, bringing equitable scientific and health benefits to Brazil and the UK.
ii)Develop a novel and effective platform to identify drug-resistant TB.
iii)Facilitate training and knowledge transfer, enhancing independent research capacity and fostering international collaborative projects.
Specific aims:
i)Enhance an existing research partnership, bringing equitable scientific and health benefits to Brazil and the UK.
ii)Develop a novel and effective platform to identify drug-resistant TB.
iii)Facilitate training and knowledge transfer, enhancing independent research capacity and fostering international collaborative projects.
Planned Impact
N/A
Organisations
- University of Cambridge (Lead Research Organisation)
- PUBLIC HEALTH ENGLAND (Collaboration)
- University of Groningen (Collaboration)
- The Wellcome Trust Sanger Institute (Collaboration)
- University of Dundee (Collaboration)
- Gene Laboratory (Collaboration)
- IMPERIAL COLLEGE LONDON (Collaboration)
- UNIVERSITY OF CAMBRIDGE (Collaboration)
- Fundação Ezequiel Dias (Collaboration)
- University of Bath (Collaboration)
- National Institute of Allergy and Infectious Diseases (NIAID) (Collaboration)
- University of Cape Town (Collaboration)
- Universidade de São Paulo (Project Partner)
- Oswaldo Cruz Foundation (Project Partner)
Publications
Airey E
(2021)
Identifying Genotype-Phenotype Correlations via Integrative Mutation Analysis.
in Methods in molecular biology (Clifton, N.J.)
Al-Jarf R
(2021)
pdCSM-cancer: Using Graph-Based Signatures to Identify Small Molecules with Anticancer Properties.
in Journal of chemical information and modeling
Albanaz ATS
(2017)
Combating mutations in genetic disease and drug resistance: understanding molecular mechanisms to guide drug design.
in Expert opinion on drug discovery
Aljarf R
(2022)
Understanding and predicting the functional consequences of missense mutations in BRCA1 and BRCA2
in Scientific Reports
Blundell TL
(2017)
Protein crystallography and drug discovery: recollections of knowledge exchange between academia and industry.
in IUCrJ
Chan DS
(2017)
Fragment Screening against the EthR-DNA Interaction by Native Mass Spectrometry.
in Angewandte Chemie (International ed. in English)
Coelho MB
(2016)
Functional interactions between polypyrimidine tract binding protein and PRI peptide ligand containing proteins.
in Biochemical Society transactions
Copoiu L
(2020)
ProCarbDB: a database of carbohydrate-binding proteins.
in Nucleic acids research
Jatana N
(2020)
Human LC3 and GABARAP subfamily members achieve functional specificity via specific structural modulations.
in Autophagy
| Description | Cambridge-Chennai centre partnership on antimicrobial resistant tuberculosis |
| Amount | £1,007,929 (GBP) |
| Funding ID | MR/N501864/1 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 03/2015 |
| End | 06/2019 |
| Description | MRC antimicrobial resistance collaboration |
| Amount | £1,588,479 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | |
| Description | Newton Fund MRC-UK DBT-India |
| Amount | £1,159,686 (GBP) |
| Funding ID | RG77600, Project: RCAG/623 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 09/2015 |
| End | 09/2018 |
| Description | Newton Researcher Links Workshop Grants |
| Amount | £34,000 (GBP) |
| Funding ID | 216419211 |
| Organisation | British Council |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 04/2016 |
| End | 01/2017 |
| Description | UK Rapid Support Team |
| Amount | £11,999,339 (GBP) |
| Organisation | National Institute for Health Research |
| Department | NIHR Biomedical Research Centre |
| Sector | Public |
| Country | United Kingdom |
| Start | |
| Description | Wellcome Collaborative Award |
| Amount | £2,341,255 (GBP) |
| Organisation | Wellcome Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 04/2019 |
| End | 03/2024 |
| Description | Wellcome Trust |
| Amount | £250,000 (GBP) |
| Organisation | Wellcome Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 04/2016 |
| End | 03/2020 |
| Description | Wellcome Trust |
| Amount | £250,000 (GBP) |
| Organisation | Wellcome Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 06/2015 |
| End | 05/2019 |
| Title | mCSM and mCSMlig |
| Description | A machine learning approach to understanding the mechanisms by which mutations affect human genetic disease, drug resistance in cancer and antimicrobial resistance in human and infectious disease |
| Type Of Material | Model of mechanisms or symptoms - human |
| Year Produced | 2015 |
| Provided To Others? | Yes |
| Impact | Demonstration that both genetic disease and drug resistance mechanisms include allosteric and protein interface affects, leading to suggestions about novel therapeutic mechanisms. |
| URL | http://bleoberis.bioc.cam.ac.uk/mcsm/ |
| Title | Chopin |
| Description | Database of the structural proteome of Mycobacterium tuberculosis |
| Type Of Material | Database/Collection of data |
| Year Produced | 2016 |
| Provided To Others? | Yes |
| Impact | Helpful in understanding the druggability of targets for antibacterials for tuberculosis |
| URL | http://mordred.bioc.cam.ac.uk/chopin/about |
| Title | Credo |
| Description | A database of protein interactions, including protein-protein, protein ligand |
| Type Of Material | Database/Collection of data |
| Year Produced | 2013 |
| Provided To Others? | Yes |
| Impact | Used to understand drug interactions with protein targets |
| URL | http://marid.bioc.cam.ac.uk/credo |
| Title | pkCSM |
| Description | pkCSM is a novel, freely available method for predicting the pharmacokinetics and toxicity of small molecules- major limiting factors in drug development. |
| Type Of Material | Computer model/algorithm |
| Year Produced | 2015 |
| Provided To Others? | Yes |
| Impact | The server has been reviewed in a commentary in Science Translational Medicine, and is currently receiving over 7000 hits/month from academic and pharmaceutical sites around the world. |
| URL | http://bleoberis.bioc.cam.ac.uk/pkcsm/ |
| Description | Cambridge UKCRC Consortium |
| Organisation | Imperial College London |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | The Cambridge UKCRC Consortium is funded via the UKCRC TIRI to develop and implement whole genome sequencing of MRSA in clinical practice. I lead this Consortium. |
| Collaborator Contribution | The partners each bring unique skills to the project, including informatics analysis, modelling, and evolutionary biology. |
| Impact | The publications to date are listed under this grant. |
| Start Year | 2011 |
| Description | Cambridge UKCRC Consortium |
| Organisation | Public Health England |
| Country | United Kingdom |
| Sector | Public |
| PI Contribution | The Cambridge UKCRC Consortium is funded via the UKCRC TIRI to develop and implement whole genome sequencing of MRSA in clinical practice. I lead this Consortium. |
| Collaborator Contribution | The partners each bring unique skills to the project, including informatics analysis, modelling, and evolutionary biology. |
| Impact | The publications to date are listed under this grant. |
| Start Year | 2011 |
| Description | Cambridge UKCRC Consortium |
| Organisation | The Wellcome Trust Sanger Institute |
| Country | United Kingdom |
| Sector | Charity/Non Profit |
| PI Contribution | The Cambridge UKCRC Consortium is funded via the UKCRC TIRI to develop and implement whole genome sequencing of MRSA in clinical practice. I lead this Consortium. |
| Collaborator Contribution | The partners each bring unique skills to the project, including informatics analysis, modelling, and evolutionary biology. |
| Impact | The publications to date are listed under this grant. |
| Start Year | 2011 |
| Description | Cambridge UKCRC Consortium |
| Organisation | University of Bath |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | The Cambridge UKCRC Consortium is funded via the UKCRC TIRI to develop and implement whole genome sequencing of MRSA in clinical practice. I lead this Consortium. |
| Collaborator Contribution | The partners each bring unique skills to the project, including informatics analysis, modelling, and evolutionary biology. |
| Impact | The publications to date are listed under this grant. |
| Start Year | 2011 |
| Description | Cambridge UKCRC Consortium |
| Organisation | University of Cambridge |
| Department | Department of Veterinary Medicine |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | The Cambridge UKCRC Consortium is funded via the UKCRC TIRI to develop and implement whole genome sequencing of MRSA in clinical practice. I lead this Consortium. |
| Collaborator Contribution | The partners each bring unique skills to the project, including informatics analysis, modelling, and evolutionary biology. |
| Impact | The publications to date are listed under this grant. |
| Start Year | 2011 |
| Description | Cambridge UKCRC Consortium |
| Organisation | University of Groningen |
| Country | Netherlands |
| Sector | Academic/University |
| PI Contribution | The Cambridge UKCRC Consortium is funded via the UKCRC TIRI to develop and implement whole genome sequencing of MRSA in clinical practice. I lead this Consortium. |
| Collaborator Contribution | The partners each bring unique skills to the project, including informatics analysis, modelling, and evolutionary biology. |
| Impact | The publications to date are listed under this grant. |
| Start Year | 2011 |
| Description | Fundação Ezequiel Dias (Funed) |
| Organisation | Fundação Ezequiel Dias |
| Country | Brazil |
| Sector | Public |
| PI Contribution | We have provided expertise in genomic DNA isolation, and will sequence and analyse the respective strains. |
| Collaborator Contribution | They have provided genomic DNA from TB strains collected throughout Brazil. |
| Impact | So far 24 TB genomes have been shipped to the UK for analysis |
| Start Year | 2015 |
| Description | Identifying targets from phenotypic screening in tuberculosis |
| Organisation | University of Dundee |
| Department | College of Life Sciences |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Collaboration Funded by Gates Foundation to identification of new targets for drug discovery arising from phenotypic screens. My team has contributed knowledge, databases and software focusing on protein targets in Mycobacterium tuberculosis |
| Collaborator Contribution | Dundee has contributed software and expertise in medicinal chemistry |
| Impact | Talks in meetings identified elsewhere by various participants. Discussions with HIT-TB Consortium |
| Start Year | 2013 |
| Description | Laboratório Gene |
| Organisation | Gene Laboratory |
| Country | Brazil |
| Sector | Academic/University |
| PI Contribution | Analysing genetic mutations identified by Professor Sergio Pena and his team. |
| Collaborator Contribution | Identification of novel genetic mutations and validation of our predictions. |
| Impact | This is multi-disciplinary- involving clinicians, geneticists, bioinformaticians and experimentalists. To date one paper has been submitted. |
| Start Year | 2015 |
| Description | Shorten-TB |
| Organisation | National Institute of Allergy and Infectious Diseases (NIAID) |
| Country | United States |
| Sector | Public |
| PI Contribution | Analysis of structure, function and druggability of targets in tuberculosis |
| Collaborator Contribution | Drug screening and development |
| Impact | None yet |
| Start Year | 2017 |
| Description | Shorten-TB |
| Organisation | University of Cape Town |
| Department | Institute of Infectious Disease and Molecular Medicine (IIDMM) |
| Country | South Africa |
| Sector | Academic/University |
| PI Contribution | Analysis of structure, function and druggability of targets in tuberculosis |
| Collaborator Contribution | Drug screening and development |
| Impact | None yet |
| Start Year | 2017 |
| Description | Shorten-TB |
| Organisation | University of Dundee |
| Department | College of Life Sciences |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Analysis of structure, function and druggability of targets in tuberculosis |
| Collaborator Contribution | Drug screening and development |
| Impact | None yet |
| Start Year | 2017 |
| Title | mCSM |
| Description | Machine learning approach to predicting the impacts of mutations on protein stability and interactions with other proteins, nucleic acids, and small molecule ligands. |
| Type Of Technology | Webtool/Application |
| Year Produced | 2016 |
| Impact | It has significant impact on understanding mutations in genetic disease and drug resistance |
| URL | http://bleoberis.bioc.cam.ac.uk/mcsm/ |
| Title | sdm |
| Description | An updated webserver for the improved SDM, used for predicting the effects of mutations on protein stability. We have updated the environment-specific amino-acid substitution tables based on the current expanded PDB (a 5 fold increases in information), and introduced new residue conformations and interaction parameters, including packing density and residue depth. |
| Type Of Technology | Webtool/Application |
| Year Produced | 2017 |
| Impact | The updated server has been extensively tested using a wide benchmark containing 2690 point mutations from 132 different protein structures. Using an established benchmark, the revised method correlated well against the hypothetical reverse mutations, better than comparable methods built using machine-learning approaches, highlighting the strength of our knowledge-based approach for identifying stabilising mutations. Given a PDB file (a Protein Data Bank file format containing the three-dimensional coordinates of the protein atoms), and a point mutation, the server calculates the stability difference score between the wildtype and mutant protein. |
| URL | http://structure.bioc.cam.ac.uk/sdm2 |
| Description | Antimicrobial Resistance Workshop |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Workshop discussing with policy makers, clinicians, scientists and research students in order to understand and cobalt impacts of antimicrobial resistance, mainly in tuberculosis |
| Year(s) Of Engagement Activity | 2016 |
| Description | BIOINFORMÁTICA ESTRUTURAL DE PROTEÍNAS: MODELOS, ALGORITMOS E APLICAÇÕES BIOTECNOLÓGICAS, Belo Horizonte, Brasil |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Professional Practitioners |
| Results and Impact | A joint Brazil-UK workshop bringing together discussion human genetics and race in Brazil with our analyses of the effects of genome mutations on genetic disease, cancer and antimicrobial resistance |
| Year(s) Of Engagement Activity | 2015 |
| Description | Cambridge Therapeutics Forum: Pharma, Biotech, Clinical School and University |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Industry/Business |
| Results and Impact | A short presentation by Tom Blundell to a mixed group involved in research ecosystems. Exemplified by foundation of Astex in my lab, progression to science park, candidate drugs into man, phase III, sale for $886million. The second talk given by Sir Greg Winter, |
| Year(s) Of Engagement Activity | 2015 |
| URL | http://www.onenucleus.com/cambridge-new-therapeutics-forum |
| Description | Indian National Science Congress 2016, Mysore |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Policymakers/politicians |
| Results and Impact | General theme: Science & Technology for Indigenous Development in India. Tom Blundell Plenary Lecturer on Drug discovery for infectious disease in India where budgets have to be low. Open Source Drug Discovery, Biotech Spin-outs and Academia in Research Ecosystems |
| Year(s) Of Engagement Activity | 2016 |
| URL | http://www.isc103.in |
| Description | School Visit by Tom Blundell (Suffolk) |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Public/other audiences |
| Results and Impact | Talk and opening a plaque to Dorothy Hodgkin commemorating her attendance at a secondary school in Beccles. Designed to encourage young students to do science - with local MP and relatives of Dorothy. Extensive media coverage in local papers. |
| Year(s) Of Engagement Activity | 2015 |
| Description | Science festival event (2015) |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Public/other audiences |
| Results and Impact | Sharon Peacock organised for the actor Stephen McGann to give a presentation as part of the Cambridge Science Festival 2015 entitled: 'Infectious knowledge:science in popular culture' He is a keen science communicator and spoke about the power of science and its place at the heart of public conversation. There was a good discussion between presenter and audience at the end. Feedback gathered at the end of the talk was generally very positive: This event was really well suited to an audience of teens and could have been marketed as such. Absolutely brilliant, interesting lecture! Really enjoyed this event. Infectious Knowledge: I was disappointed in the simplistic approach to science, but that's popular culture. |
| Year(s) Of Engagement Activity | 2015 |
| URL | http://www.sciencefestival.cam.ac.uk/system/files/csf_2015_web_programme.pdf |
| Description | Tom Blundell appointed 8th Distinguished Technopreneur 2015, Singapore |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Policymakers/politicians |
| Results and Impact | A discussion by Tom Blundell of research ecosystems, based on experience of forming companies in London and Cambridge, and looking at options for Singapore. Discussions with Deputy Prime Minister of Singapore; visit of Head of Research to my company on the Science Park |
| Year(s) Of Engagement Activity | 2015 |
| URL | http://www.science50.com.sg/dts.html |
| Description | Two lectures in University Pretoria, first to broad audience of students, policy makers, teachers; the second to students from the local Ndebele township |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Undergraduate students |
| Results and Impact | Lectures leading to small discussions with groups of mainly Ndebele speaking undergraduate students; followed by visit to local township for discussions mediated by Dr Gugu Motshwene, and ex-tudent now lecturer in the University of Pretoria |
| Year(s) Of Engagement Activity | 2016 |
| Description | Weaver Endowed Lecture at UC Davis California |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Public/other audiences |
| Results and Impact | A general lecture to a broad audience about the contributions of my science to drug discovery over the past 50 years |
| Year(s) Of Engagement Activity | 2016 |
| Description | Wellcome Trust Sanger Institute Genomics for Clinicians course |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | A talk on pathogen genomics to clinical professionals attending a 1 week course to gain an understanding of the application of genomics to clinical practice |
| Year(s) Of Engagement Activity | 2017 |